Enzymes Involved in Processing Glutathione Conjugates

Many potentially toxic electrophiles react with glutathione to form glutathione S-conjugates in reactions catalyzed or enhanced by glutathione S-transferases. The glutathione S-conjugate is sequentially converted to the cysteinylglycine-, cysteine- and N-acetyl-cysteine S-conjugate (mercapturate). The mercapturate is generally more polar and water soluble than the parent electrophile and is readily excreted. Excretion of the mercapturate represents a detoxication mechanism. Some endogenous compounds, such as leukotrienes, prostaglandin (PG) A2, 15-deoxy-Δ(12,14)-PGJ(2), and hydroxynonenal can also be metabolized to mercapturates and excreted. On occasion, however, formation of glutathione S- and cysteine S-conjugates are bioactivation events as the metabolites are mutagenic and/or cytotoxic. When the cysteine S-conjugate contains a strong electron-withdrawing group attached at the sulfur, it may be converted by cysteine S-conjugate β-lyases to pyruvate, ammonium and the original electrophile modified to contain an –SH group. If this modified electrophile is highly reactive then the enzymes of the mercapturate pathway together with the cysteine S-conjugate β-lyases constitute a bioactivation pathway. Some endogenous halogenated environmental contaminants and drugs are bioactivated by this mechanism. Recent studies suggest that coupling of enzymes of the mercapturate pathway to cysteine S-conjugate β-lyases may be more common in nature and more widespread in the metabolism of electrophilic xenobiotics than previously realized.